Kawasaki Hospital Research Center, Kawasaki Medical School, Okayama, Japan.
PLoS One. 2013 Aug 16;8(8):e71093. doi: 10.1371/journal.pone.0071093. eCollection 2013.
Midkine (MDK) is a heparin-binding growth factor that is highly expressed in many malignant tumors, including lung cancers. MDK activates the PI3K pathway and induces anti-apoptotic activity, in turn enhancing the survival of tumors. Therefore, the inhibition of MDK is considered a potential strategy for cancer therapy. In the present study, we demonstrate a novel small molecule compound (iMDK) that targets MDK. iMDK inhibited the cell growth of MDK-positive H441 lung adenocarcinoma cells that harbor an oncogenic KRAS mutation and H520 squamous cell lung cancer cells, both of which are types of untreatable lung cancer. However, iMDK did not reduce the cell viability of MDK-negative A549 lung adenocarcinoma cells or normal human lung fibroblast (NHLF) cells indicating its specificity. iMDK suppressed the endogenous expression of MDK but not that of other growth factors such as PTN or VEGF. iMDK suppressed the growth of H441 cells by inhibiting the PI3K pathway and inducing apoptosis. Systemic administration of iMDK significantly inhibited tumor growth in a xenograft mouse model in vivo. Inhibition of MDK with iMDK provides a potential therapeutic approach for the treatment of lung cancers that are driven by MDK.
中期因子（MDK）是一种肝素结合生长因子，在许多恶性肿瘤中高度表达，包括肺癌。MDK 激活 PI3K 通路并诱导抗凋亡活性，从而增强肿瘤的存活能力。因此，抑制 MDK 被认为是癌症治疗的一种潜在策略。在本研究中，我们展示了一种针对 MDK 的新型小分子化合物（iMDK）。iMDK 抑制了携带致癌 KRAS 突变的 MDK 阳性 H441 肺腺癌细胞和不可治疗的肺鳞癌细胞 H520 的细胞生长，这两种细胞都是不可治疗的肺癌类型。然而，iMDK 并没有降低 MDK 阴性 A549 肺腺癌细胞或正常人类肺成纤维细胞（NHLF）的细胞活力，表明其具有特异性。iMDK 抑制了内源性 MDK 的表达，但不抑制其他生长因子，如 PTN 或 VEGF。iMDK 通过抑制 PI3K 通路和诱导细胞凋亡来抑制 H441 细胞的生长。iMDK 的全身给药在体内异种移植小鼠模型中显著抑制了肿瘤生长。用 iMDK 抑制 MDK 为 MDK 驱动的肺癌的治疗提供了一种潜在的治疗方法。
